Novel therapeutic approaches targeting L-type amino acid transporters for cancer treatment

L-type amino acid transporters(LATs) mainly assist the uptake of neutral amino acids into cells. Four LATs(LAT1, LAT2, LAT3 and LAT4) have so far been identified. LAT1(SLC7A5) has been attracting much attention in the field of cancer research since it is commonly up-regulated in various cancers. Basic research has made it increasingly clear that LAT1 plays a predominant role in malignancy. The functional significance of LAT1 in cancer and the potential therapeutic application of the features of LAT1 to cancer management are described in this review.

The RALF1-FERONIA complex interacts with and activates TOR signaling in response to low nutrients

Target of rapamycin(TOR)kinase is an evolutionarily conserved major regulator of nutrient metabolism and organismal growth in eukaryotes.In plants,nutrients are remobilized and reallocated between shoots and roots under low-nutrient conditions,and nitrogen and nitrogen-related nutrients(e.g.,amino acids)are key upstream signals leading to TOR activation in shoots under low-nutrient conditions.However,how these forms of nitrogen can be sensed to activate TOR in plants is still poorly understood.Here we report that the Arabidopsis receptor kinase FERON IA(FER)interacts with the TOR pathway to regulate nutrient(nitrogen and amino acid)signaling under low-nutrient conditions and exerts similar metabolic effects in response to nitrogen deficiency.We found that FER and its partner,RPM1-induced protein kinase(RIPK),interact with the TOR/RAPTOR complex to positively modulate TOR signaling activity.During this process,the receptor complex FER/RIPK phosphorylates the TOR complex component RAPTOR1B.The RALF1 peptide,a ligand of the FER/RIPK receptor complex,increases TOR activation in the young leaf by enhancing FER-TOR interactions,leading to promotion of true leaf growth in Arabidopsis under lownutrient conditions.Furthermore,we showed that specific amino acids(e.g.,Gin,Asp,and Gly)promote true leaf growth under nitrogen-deficient conditions via the FER-TOR axis.Collectively,our study reveals a mechanism by which the RALF1-FER pathway activates TOR in the plant adaptive response to low nutrients and suggests that plants prioritize nutritional stress response over RALF1-mediated inhibition of cell growth under low-nutrient conditions.

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice

PEGylated-L-asparaginase(PEG-ASNase)is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia(ALL).Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis,with obesity and older age considered risk factors of the injury.Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury.Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1,3,5,and 7 days after drug administration.Liver triglycerides were quantified,and plasma bilirubin,ALT,AST,and non-esterified fatty acids(NEFA)were measured.The mRNA and protein levels of genes involved in hepatic fatty acid synthesis,β-oxidation,very low-density lipoprotein(VLDL)secretion,and white adipose tissue(WAT)lipolysis were determined.Mice developed hepatic steatosis after PEG-ASNase,which associated with increases in bilirubin,ALT,and AST.The hepatic genes Ppara,Lcad/Mcad,Hadhb,Apob100,and Mttp were upregulated,and Srebp-1 c and Fas were downregulated after PEG-ASNase.Increased plasma NEFA,WAT loss,and adipose tissue lipolysis were also observed after PEG-ASNase.Furthermore,we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice,consistent with clinical studies of ASNase-induced liver injury.Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.